A major challenge in the reconstruction of tooth-supporting alveolar bone defects is the simultaneous restoration of bone, cementum and a functional periodontal ligament (PDL). To date, significant limitations exist with the predictability and extent of repair achievable via current regenerative periodontal therapies. We have demonstrated through the support of the NIDCR that gene therapy has strong potential to target and deliver growth-promoting factors (such as platelet-derived growth factor, bone morphogenetic proteins and LIM domain mineralization protein) to stimulate the re-engineering of periodontal defects. Further, by employment of emerging technologies in image-based scaffold design to address the complex topography of periodontal defects, we propose to employ customized biomimetic scaffolding strategies to repair periodontal wounds. The goal of this competitive renewal is to enhance novel gene delivery regenerative medicine strategies and apply them to relevant models of oral and periodontal disease. The specific aims of this proposal are: Specific Aim 1: Development of vector and image-based hybrid scaffolding constructs to repair tooth- supporting structures using ex vivo and in vivo models. Hypothesis: The controlled delivery of growth factor genes using computational design of hybrid scaffolds with fiber-oriented channels at the tooth-bone interface will stimulate and guide bone, ligament and cementum formation. A comparison of using direct versus reactive polymer coatings to facilitate growth factor gene delivery will be evaluated in vivo to repair periodontal defects. We will employ a bioconjugation process to functionalize biomaterials for the delivery of growth factors such as PDGF and BMPs to tissue engineer periodontia. Specific Aim 2: To use regional gene delivery methods via imaged-based scaffold design in experimental periodontal disease in canines. Hypothesis. The development of image-based scaffolds that can adapt to the tooth-bone interface and improve the bioavailability of growth factor genes at periodontal wound sites. We will utilize a ligature-induced model of periodontal disease to create periodontal osseous defects. We will then employ gene delivery technologies from SA #1 to use image-based hybrid scaffolds to promote periodontal repair. The results of these investigations should build on the body of evidence that our group has achieved in the field on periodontal tissue engineering. The findings from these investigations will well position us to apply this technology to the human clinical trial setting and submit a human clinical trial planning grant for a first-in-human investigation. PUBLIC HEALTH RELEVANCE: This investigation seeks to continue the development of novel regenerative medicine strategies to reconstruct periodontal (tooth-supporting) bone defects in the jaws. This approach offers significant potential to treat patients afflicted with periodontitis, a common oral infectious disease affecting over 50% of the U.S. Population. As such, these studies support the NIH mission of the promotion of public health towards development of improved therapies to treat human disease.